PROJECT SUMMARY The motivation to eat depends on the relative balance of activity between orexigenic (appetite inducing) and anorexigenic (appetite suppressing) brain systems. An abnormal balance of activity in these systems can lead to substantial health problems with high associated economic costs. In the United States, over half the population is considered overweight, and the aggregate economic cost is estimated in excess of $60 billion per year. Undernourishment is also a substantial problem: abnormal appetite suppression, as can occur during infection, old age, and cancer, can lead to severely low body weight and malnutrition. However, despite obvious importance, the neural basis of hunger and appetite suppression continues to be poorly understood at a neuronal or circuit level, and is currently an important focus of investigation. We recently discovered that a population of neurons in the parasubthalamic nucleus (PSTN) sends substantial monosynaptic axonal projections to neurons in the parabrachial nucleus (PBN) that express calcitonin gene related peptide (?PBN CGRP neurons?) and are well known to be necessary and sufficient for normal appetite suppression following a meal, during gastrointestinal distress, and during infection. Previous studies investigating the PSTN are minimal, but they suggest that these neurons may play a role in appetite suppression. Therefore, the purpose of this proposal is to characterize the role of PSTN neurons in food intake behavior. In Aim 1, we will test the hypothesis that multiple forms of appetite suppression cause an increase in activity in PSTN neurons. In Aim 2, we will test the hypothesis that stimulation of PSTN neurons is sufficient to decrease food intake. We will also test the hypothesis that stimulation of projections from the PSTN to the PBN is sufficient to decrease food intake. In Aim 3, we will test the hypothesis that inhibition of PSTN neurons will increase food intake during baseline conditions and during conditions of appetite suppression. To pursue these Aims, we will use cutting edge viral gene delivery tools and genetically encoded neuronal actuators to provide new insights into how the brain regulates appetite.